Myoferlin Regulates Wnt/β-Catenin Signaling-Mediated Skeletal Muscle Development by Stabilizing Dishevelled-2 Against Autophagy
Myoferlin Regulates Wnt/β-Catenin Signaling-Mediated Skeletal Muscle Development by Stabilizing Dishevelled-2 Against Autophagy
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DOI：
10.3390/ijms20205130
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发表时间：
2019-10-02
影响因子：
5.6
通讯作者：
Yin, Huadong
中科院分区：
文献类型：
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作者：
Han, Shunshun;Cui, Can;Yin, Huadong
肌钙蛋白（MyoF）是一种在心脏和肌肉组织中表达的钙/磷脂结合蛋白，属于肌钙蛋白家族。虽然MyoF促进成肌细胞分化，但其潜在机制尚不清楚。我们发现MyoF不仅能促进C2C12成肌细胞分化，还能抑制肌肉萎缩和自噬。在本研究中，我们发现在缺乏MyoF的情况下，成肌细胞由于分化缺陷而不能发育成成熟的肌管。同时，MyoF调节萎缩相关基因（Atrogin-1和MuRF1）的表达，挽救肌肉萎缩。此外，MyoF与disheveled -2 （Dvl-2）相互作用以激活典型Wnt信号。MyoF通过降低lc3标记的Dvl-2水平和拮抗自噬系统促进Dvl-2泛素化抗性。综上所述，我们发现骨骼肌萎缩过程中MyoF在成肌细胞分化中起重要作用。在分子水平上，MyoF保护Dvl-2免受自噬介导的降解，从而促进Wnt/ β -连环蛋白信号通路的激活。总之，我们的研究结果表明，MyoF通过稳定Dvl-2和防止自噬，调节Wnt/ β -连环蛋白信号介导的骨骼肌发育。
Myoferlin (MyoF), which is a calcium/phospholipid-binding protein expressed in cardiac and muscle tissues, belongs to the ferlin family. While MyoF promotes myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that MyoF not only promotes C2C12 myoblast differentiation, but also inhibits muscle atrophy and autophagy. In the present study, we found that myoblasts fail to develop into mature myotubes due to defective differentiation in the absence of MyoF. Meanwhile, MyoF regulates the expression of atrophy-related genes (Atrogin-1 and MuRF1) to rescue muscle atrophy. Furthermore, MyoF interacts with Dishevelled-2 (Dvl-2) to activate canonical Wnt signaling. MyoF facilitates Dvl-2 ubiquitination resistance by reducing LC3-labeled Dvl-2 levels and antagonizing the autophagy system. In conclusion, we found that MyoF plays an important role in myoblast differentiation during skeletal muscle atrophy. At the molecular level, MyoF protects Dvl-2 against autophagy-mediated degradation, thus promoting activation of the Wnt/beta-catenin signaling pathway. Together, our findings suggest that MyoF, through stabilizing Dvl-2 and preventing autophagy, regulates Wnt/beta-catenin signaling-mediated skeletal muscle development.